16-53605526-C-T

Variant names:

• chr16-53605526-C-T
• rs3213758
• NM_015272.5:c.3790G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015272.5(RPGRIP1L):​c.3790G>A​(p.Asp1264Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,892 control chromosomes in the GnomAD database, including 4,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1264S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (395 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4115 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.23
• Publications: 50 publications found

Genes affected

RPGRIP1L (HGNC:29168): (RPGRIP1 like) The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). [provided by RefSeq, Jun 2016]

RPGRIP1L Gene-Disease associations (from GenCC):

• Meckel syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Joubert syndrome 7

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with renal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065824986).
• BP6: Variant 16-53605526-C-T is Benign according to our data. Variant chr16-53605526-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3790G>A	p.Asp1264Asn	missense_variant	Exon 26 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.3790G>A	p.Asp1264Asn	missense_variant	Exon 26 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 7755 AN: 152082 Hom.: 395 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.0763

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0729 AC: 18333 AN: 251334 AF XY: 0.0714

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.0675

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.0442

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0602

GnomAD4 exome AF: 0.0622 AC: 90897 AN: 1461694 Hom.: 4115 Cov.: 32 AF XY: 0.0622 AC XY: 45237 AN XY: 727180

African (AFR) AF: 0.00968 AC: 324 AN: 33480

American (AMR) AF: 0.0641 AC: 2869 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 1560 AN: 26134

East Asian (EAS) AF: 0.278 AC: 11043 AN: 39700

South Asian (SAS) AF: 0.0693 AC: 5977 AN: 86258

European-Finnish (FIN) AF: 0.0457 AC: 2440 AN: 53418

Middle Eastern (MID) AF: 0.0265 AC: 153 AN: 5766

European-Non Finnish (NFE) AF: 0.0560 AC: 62261 AN: 1111824

Other (OTH) AF: 0.0707 AC: 4270 AN: 60390

GnomAD4 genome AF: 0.0510 AC: 7756 AN: 152198 Hom.: 395 Cov.: 32 AF XY: 0.0515 AC XY: 3830 AN XY: 74410

African (AFR) AF: 0.0128 AC: 531 AN: 41550

American (AMR) AF: 0.0517 AC: 791 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3468

East Asian (EAS) AF: 0.302 AC: 1555 AN: 5148

South Asian (SAS) AF: 0.0757 AC: 364 AN: 4808

European-Finnish (FIN) AF: 0.0414 AC: 439 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0545 AC: 3705 AN: 68006

Other (OTH) AF: 0.0569 AC: 120 AN: 2108

Alfa AF: 0.0579 Hom.: 1793

Bravo AF: 0.0521

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0551 AC: 474

ExAC AF: 0.0728 AC: 8838

Asia WGS AF: 0.188 AC: 654 AN: 3478

EpiCase AF: 0.0525

EpiControl AF: 0.0514

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joubert syndrome 7 Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Meckel syndrome, type 5 Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Joubert syndrome Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nephronophthisis 8 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.026	.;.;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.65	T;.;T;T;T;T
MetaRNN	Benign	0.0066	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;.;L;.;.
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N;.;.;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.24	T;.;.;T;T;T
Sift4G	Benign	0.070	T;.;T;D;T;T
Polyphen		0.96	D;B;.;B;.;.
Vest4		0.083
MPC		0.071
ClinPred		0.0019	T
GERP RS		1.6
Varity_R		0.050
gMVP		0.43
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3213758; hg19: chr16-53639438; COSMIC: COSV50903544;